For many years silver and silver salts have been used as antimicrobial agents. Early medicinal use of silver was the application of aqueous silver nitrate solutions to prevent eye infection in newborn babies. Silver salts, colloids, and complexes have also been used to prevent and to control infection. For example, colloidal metallic silver has been used topically for dermatitis, conjunctivitis, and infections including vaginal infections.
Other metals, such as gold, zinc, copper and cerium, have also been found to possess antimicrobial properties, both alone and in combination with silver. These and other metals have been shown to provide antimicrobial behavior even in extremely low concentrations, a property referred to as “oligodynamic.” Metal ions, especially those of heavy metals, show this effect. The exact mechanism of action is still unknown. Data from silver suggest that these ions denature enzymes of the target cell or organism by binding to reactive groups, resulting in their precipitation and inactivation. There is recent evidence of changing the cellular DNA structure itself. Silver also reacts with the amino-, carboxyl-, phosphate-, and imidazole-groups and diminish the activities of lactate dehydrogenase and glutathione peroxidase. Bacteria are in general affected by the oligodynamic effect and it seems this effect is agnostic with regard to the strain of bacteria. Viruses in general are not as sensitive to this effect.
Silver is a naturally occurring element that is present in our environment, including the air we breathe, the water we drink and the foods we consume. However, silver does not occur naturally in the tissues of humans and animals. Silver's relatively low toxicity to animals and humans. It is however, extremely toxic to simpler forms of life such as bacteria. The antibacterial properties of silver are known, and were at least suspected for thousands of years. The ancient Greeks used silver pots and other utensils. Hippocrates, the father of modern medicine, wrote that silver had beneficial healing and anti-disease properties. The Phoenicians stored water, wine and vinegar in silver bottles to prevent spoiling. In the early 1900s, it was not uncommon for people to place silver dollars in milk bottles to prolong the freshness of the milk. The malleability and non-toxicity of silver make it a useful material used in dental alloys for fittings and fillings.
Widespread use of silver declined with the development of modern antibiotics, many of them used to kill pathogens, but overuse has led to increased bacteria resistance. Hence, there is renewed interest in silver as a broad spectrum antimicrobial. Silver, when applied topically, demonstrates efficacy against microorganisms which sometimes exhibit resistance characteristics. There are many products on the market to treat or kill bacteria. These products are found in a variety of forms, including liquid, foam, gel, lotions and ointments.
Additionally, silver is known for antimicrobial use with dental and medical devices, such as mouthpieces, mouthguards, dental appliances, as well as catheters, cannulae, and stents. Additionally, silver compounds have been used in fluids for consumption and incorporated into both clothing and packaging for prevention of infections, bacterial growth, and spoilage.
Hospital acquired infections due to bacteria cause approximately more than 100,000 deaths annually. This number is more than the combined death total resulting from AIDS, breast cancer and automobile accidents. The economic burden is estimated to be greater than $5.2 billion annually. These infections are the fourth leading cause of death. Inadequate hand hygiene also contributes to food-related illnesses, including Salmonella and E coli infection. According to The Center for Disease Control and Prevention (hereafter, the “CDC”), as many as 76 million Americans contract a food-borne illness each year. Of these, nearly 5,000 die as a result of the illness. Others experience the annoying symptoms of nausea, vomiting and diarrhea.
Published CDC guidelines enhanced hand sanitizer sales in the United States, which experienced double-digit growth in the 2004-2010 period, according to marketing information provided by A. C. Nielsen. The total annual U.S. infection prevention industry is estimated to be $9.4 billion.
With many devices, it is preferred to have a lubricious coating on the device. Lubricious coatings aid device insertion, reduce the trauma to tissue, and reduce the adhesion of bacteria. Another drawback to conventional methods which apply silver and other metals directly onto the surface of a device for which a lubricious coating is also desired is that a second, lubricious coating must be applied to the device over the antimicrobial coating, adding to manufacturing cost and time.
Some of these coatings release, to varying degrees, silver ions into the solution or tissue surrounding the substrate.
An oligodynamic metal may be physically incorporated into a gel in a variety of ways. For example, a liquid solution of a silver salt may be dipped, sprayed or brushed onto and into mammalian skin.
Settling of particles of the oligodynamic agent occurs as a result of the size and density of the particles. Settling of the particles from such solutions can cause unpredictable changes in the concentration of the oligodynamic agent in the composition. These changes in ion concentration result in several drawbacks for producing commercial products. First, unpredictable changes in the concentration of the oligodynamic agent make it difficult to produce a composition having a specific, homogenous, exact concentration of antimicrobial ions and, thus, a particular and specific effectiveness. Additionally, these changes make it difficult to produce multiple batches of the composition having the same antibacterial concentration. Furthermore, the concentration of the antimicrobial ions can affect other properties of the composition, such as its adhesive and lubricious properties. Consistency of antimicrobial activity is essential in the production of antimicrobial devices.
Another problem associated with particle suspensions is agglomeration of the particles. Particle agglomeration produces larger particle sizes which increases settling of particles from solution.
Many researchers have attempted to overcome these problems.
U.S. Pat. No. 4,847,049 to Yamamoto and entitled “Method of Forming Chelated Collagen Having Bactericidal Properties” describes a method for protecting renatured collagen against bacterial and fungal attack. The method includes contacting the collagen with a silver ion containing solution at a pH range of 4.0 to 9.0 and exposing the silver-chelated collagen to ultraviolet radiation.
U.S. Pat. No. 7,135,195 to Holladay et al. entitled “Treatment of Humans with Colloidal Silver Composition” describes water and silver particles, wherein the silver particles comprise an interior of elemental silver and an exterior of ionic silver oxide. The silver particles are described to be present in the water at a level of about 5-40 parts per million (Hereafter, “ppm”).
U.S. Pat. No. 6,881,424 to Kemp entitled “Highly Acidic Metalated Organic Acid” teaches how to mix a monovalent or polyvalent cation and an organic acid in the presence of a strong oxyacid. The resulting composition is described to be less corrosive to a ferrous metal than a solution of a mineral acid having the same acidic pH value, and is more biocidal than a mixture of the organic acid and a metal salt of the organic acid which mixture has the same acid normality value.
U.S. Pat. No. 5,895,782 to Overton et al. is entitled “Acid Replacement Solution for Cleaning of Non Ferrous Metals” describes the use of non-ferrous alloys such as copper, brass and high strength aluminum alloys for cleaning purposes. The solution is described to be prepared by mixing Ca(OH)2 and KOH with equivalent sulfuric acid in water, and then passing the solution through a 10 micron filter.
U.S. Pat. No. 6,383,095 to Newman, et al. is entitled “Ionic Silver Complex” and describes how to combine ingredients including water, a source of free silver ions, and a substantially non-toxic, substantially thiol-free, substantially water soluble complexing agent. This patent claims the use of an alkali metal and/or alkaline earth metal used as a counter-ion.
U.S. Pat. No. 6,583,176 to Arata is entitled “Aqueous Disinfectant” and describes an aqueous solution that is formulated by electrolytically generating silver ions in water in combination with a citric acid.
Japanese patent application JP 2007230996A2 (Abstract only) and entitled “Anti-chafing composition comprising Boron Nitride” to General Electric Co., describes an anti-chafing composition for topical application comprising boron nitride.
US Patent Application No. 20080311206A1 entitled “Anti-Chafing Compositions Comprising Boron Nitride” to Student, et al. and assigned to General Electric Co., describes an anti-chafing composition for topical application comprising boron nitride.
U.S. Pat. No. 5,676,977 entitled “Method of Curing AIDS with Tetrasilver Tetroxide Molecular Crystal Devices” to Antelman and assigned to Antelman Technologies Ltd. describes a method of curing the AIDS virus using an intravenous injection using Tetrasilver Tetroxide.
Korean Patent Application KR7090732A—entitled “Anti-chafing compositions comprising Boron Nitride” to Student, et al. and assigned to General Electric Co., describes an anti-chafing composition for topical application.
U.S. Pat. No. 6,258,385 entitled “Tetrasilver Tetroxide Treatment for Skin Conditions to Antelman and assigned to Marantech Holding, LLC describes an invention that relates to the use of electron active molecular crystals comprising tetrasilver tetroxide (Ag4O4) for the treatment and cure of dermatological skin conditions.
US Application Number US20060105057 entitled “Compositions Using Tetrasilver Tetroxide and Methods for Management of Skin Conditions Using Same” to Antelman and assigned to Marantech Holding, LLC., describes pharmaceutical compositions including tetrasilver tetroxide (Ag4O4), such as in crystalline form, and methods of using such compositions for the prevention, treatment, and management of various dermatological skin conditions and diseases to include but not limited to skin chafing.
US Application Number US20040022868 entitled “Compositions Using Tetrasilver Tetroxide and Methods for Management of Skin Conditions Using Same” to Antelman and assigned Marantech Holding, LLC describes pharmaceutical compositions including tetrasilver tetroxide (Ag4O4), such as in crystalline form, and methods of using such compositions for the prevention, treatment, and management of various dermatological skin conditions and diseases to include but not limited to skin chafing.
US Application Number 20100120915A1 entitled “Antimicrobials and Related Methods to Beierle and not assigned, describes antimicrobial balms but does not mention the use of any type of silver or silver ions).
U.S. Pat. No. 7,311,927 entitled “Antiseptic Solutions Containing Silver Chelated with Polypectate and EDTA” to Miner, et al and assigned to Edwin Odell Miner, describes a liquid antiseptic and cleanser having improved long-term stability and includes silver ion in the list of ingredients.
PCT Publication Number WO2004/028461 entitled “Antiseptic Solutions Containing Silver Chelated with Polypectate and EDTA” by Miner, et al, describes a liquid antiseptic and cleanser having improved long-term stability and includes silver ions in the list of ingredients.
A PCT application to Karandiakar, WO 2006/015317, entitled “Antimicrobial Devices and Compositions” describes methods and compositions for antimicrobial devices comprising metal containing compositions which are resistant to heat and light discoloration. The metal containing compositions may comprise salts or complexes of silver, copper or zinc. In one aspect the compositions comprise silver salts. In another aspect, the compositions comprise silver complexes. In one aspect, the metal salts may comprise metal salts of saccharin, acesulfame, long chain fatty acids, and alkyl dicarboxylic acids. The compositions further comprise polymers which form salts or complexes with silver, copper or zinc. The methods of the present invention comprise treating devices with the metal containing compositions, including, but not limited to, such devices as woven wound care materials, catheters, patient care devices, and collagen matrices. A US Patent to Newman, U.S. Pat. No. 6,830,895, entitled “Ionic Silver Oxide Complex” describes an invention that relates to a substantially non-colloidal solution made by combining ingredients comprising (a) water; (b) a source of free silver ions; and (c) a substantially non-toxic, substantially thiol-free, substantially water-soluble complexing agent.
Therefore, a need has been established to provide a method for rendering a gel resistant to infection by reducing or eliminating undesirable bacteria growth primarily on the surface of the skin or for wounds or sores in the skin. It is important that the metal oxide complex is homogenously dispersed and endures throughout the life of the use of the gel and that the complex remains stable so that it can exhibit prolonged activity during shelf life. There is also a need in the art for metal oxide compositions which can be incorporated into gels to provide antimicrobial activity. There is also a need for compositions that overcome the solubility, settling, and agglomeration problems of conventional oligodynamic compositions, and exhibit enhanced, sustained release of oligodynamic agents when these agents (primarily silver oxide for the present disclosure, but copper and other metal oxides are also useful) are dispersed within gels, liquids and some solids. Incorporating the metal oxides into the products acceptable for mammalian skin application and even ingestion in a cost efficient and reproducible manner, is required for providing readily available items of manufacture and is one subject of the present disclosure.